Psoriasis is one of the most common skin diseases, affecting 2-4% of the Caucasian population worldwide. Due to its chronic nature, its often severely disfiguring aspect, and the lack of curative therapies, the disease causes considerable distress to individual patients and presents a significant cost burden to healthcare providers.
This complex disease is characterized by alterations in a variety of different cells.
These alterations include epidermal keratinocyte hyperproliferation and altered differentiation indicated by focal parakeratosis (cell nuclei in stratum corneum). Endothelial cells are also hyperproliferative resulting in angiogenesis and dilation, and express increased levels of adhesion molecules. A mixed leukocytic infiltrate is observed which is composed of activated T-lymphocytes, that produce inflammatory cytokines, as well as an increased number of dermal mast cells. In addition, activated dendritic cells are present which synthesize TNFα and IFNα, that are central to the disease. Intracutaneous secretion of cytokines is thought to mediate some or all of the tissue alterations which are observed in psoriasis. These cytokines include tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and transforming growth factor-α (TGFα). Also of particular importance is the induction of interleukin-12 (IL12), interleukin 22, and interleukin-23 (IL23).
Research into the pathogenesis of psoriatic skin lesions, and the development of potential treatments for psoriasis, have been severely hampered by the lack of appropriate animal models. Several investigators have produced transgenic animals in which the increased expression of cytokines, adhesion molecules, signalling molecules, or other proteins in the skin results in epithelial hyperproliferation, inflammatory responses of the epidermis, or altered differentiation. For example, mouse models which overexpress VEGF-A or STAT3 in the epidermis harbour the most psoriasis-like phenotype known to date (Sano et al. (2005), “Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model”, Nat. Med., 11, 43-39; and Xia et al. (2003) “Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis”, Blood, 102, 161-168). However, none of these models is based on the modelling of up- or down-regulated molecules, as they occur in psoriatic lesional skin, and therefore may only represent “phenocopies” mimicking psoriasis. Therefore, using these models to explore novel strategies of interventions may not be relevant for the human disease and, accordingly, these models have not been widely used for pre-clinical drug testing. Moreover, none of these existing models yield a 100% disease penetrance with a rapid onset of disease, further limiting their use in high throughput screening. Finally, human psoriasis flare-ups are commonly triggered by environmental factors. One of the most important “classical” triggers of psoriasis is the so-called Koebner phenomenon which refers to the elicitation of skin pathology by mechanical trauma such as habitual friction on exposed joints, minor cuts, or surgical wounds. None of the existing animal models have been shown to exhibit a Koebner phenomenon.
Another known animal model uses human psoriatic skin transplanted onto the skin of a scid mouse. In these animal models, the transplanted skin grafts reportedly implant with greater than 85% graft survival and continue to exhibit psoriatic features for at least six weeks after transplantation. However, this animal model is difficult to utilize as a screening method for therapeutic agents as it requires human skin for transplantation to generate the model. Thus, there are no prior models of psoriasis in which the clinical and histopathological phenotype are known to develop as the result of recreating the overexpression of a gene which is known to be overexpressed in lesional psoriatic skin.
There is, therefore, an unmet need for an animal model which is suitable for investigations into psoriasis. Any such model should reproduce the clinical and histopathological phenotype of human psoriasis to as large an extent as possible. The model should be useful for research and for screening test substances which may be useful for the treatment of psoriasis. The invention aims to provide such a model and also extends to animal models which are relevant to other inflammatory skin conditions.